Recent applications of gem-dichloroepoxide intermediates in synthesis

Issue in Honor of Prof. Anthony J. Arduengo, III ARKIVOC 2012 (ii) 24-40

Page 24 ©ARKAT-USA, Inc.

Recent applications of gem-dichloroepoxide intermediates

in synthesis

Timothy S. Snowden*

Department of Chemistry, The University of Alabama,

Box 870336, Tuscaloosa, AL, USA 35487-0336

E-mail: [email protected]

Dedicated to Professor Anthony J. Arduengo, III on the occasion of his 60th birthday

DOI: http://dx.doi.org/10.3998/ark.5550190.0013.204

Abstract

This review highlights recent synthetic applications of the Jocic-Reeve, Corey-Link, and

Bargellini reactions, all of which proceed through reactive gem-dichloroepoxide intermediates.

Research published between 2001-early 2011 involving enhancements to the named reactions,

new synthetic methods, target-directed synthesis, and drug discovery and development is

emphasized.

Keywords: Dichloroepoxide, dichlorooxirane, Jocic, Reeve, Corey-Link, Bargellini,

trichloromethyl carbinol

Table of Contents

1. Introduction

2. Jocic (Jocic-Reeve) Reactions

3. Corey-Link and Modified Corey-Link Reactions

4. Bargellini Reactions

5. Conclusion

6. Acknowledgements

7. References

mailto:[email protected]

http://dx.doi.org/10.3998/ark.5550190.0013.204


5 ©ARKAT-USA, Inc.

1. Introduction

Dichloroepoxides are intermediates common to several named reactions including the Jocic

(Jocic-Reeve),1 Corey-Link,2 and Bargellini3 reactions. In all three cases, 2-substituted

carboxylic acids or acid derivatives are produced. The named reactions are differentiated by the

substrates involved, subtle variances in mechanism, or the products obtained. Coincidentally, all

three methods appear to have become “named reactions” through third party classification of

each reaction by its respective discoverer(s) in separate 1998 publications.4 In the Jocic-Reeve

and Corey-Link reactions, the intermediate gem-dichloroepoxides are formed in situ by treatment

of readily accessible trichloromethyl carbinols (2) with base in protic or mixed media (Scheme

1). Nucleophiles readily undergo regioselective substitution at the α-carbon (non-chloride

bearing position) of the oxiranes (4) leading to formation of α-substituted acid chlorides (5). The

acid chlorides are subject to nucleophilic acyl substitution, including solvolysis, affording a

variety of possible carboxylic acid derivatives (6) or heterocycles depending upon the reaction

conditions used. Product yields are typically high, although alternative reaction paths are known

to compete upon slight modifications of reaction conditions.5

Scheme 1. General mechanism of reactions involving gem-dichloroepoxides (4).

The Corey-Link reaction is a specific example of the much broader and more general Jocic-

Reeve reaction. In the Corey-Link approach, asymmetric trichloromethyl carbinols are treated

with azide to from chiral α-azido carboxylic acid derivatives.2 These products are often

subsequently reduced to furnish unnatural α-amino acids in high yields. The Corey-Link reaction

is arguably the most popular and recognizable of the reactions involving gem-dichloroepoxide

intermediates.

Whereas Jocic-Reeve and commonly, although not exclusively, Corey-Link reactions begin

by treating secondary trichloromethyl carbinols (2 where R1 or R2 = H) with base, the Bargellini

reaction typically involves addition of a sterically accessible ketone to trichloromethide (formed

by deprotonation of added chloroform with hydroxide or DBU) resulting in an α-trichloromethyl

tertiary alkoxide (3). The alkoxide rapidly forms the gem-dichloroepoxide (4) without

necessitating isolation of the carbinol 2 (Scheme 1). A key application of this reaction is the



preparation of hindered α-substituted carboxylic acid derivatives that may be difficult to prepare

by direct nucleophilic substitution with congested 2-halocarboxylic acid derivatives.

The reaction sequence from intermediate 3 to product 6 highlighted in Scheme 1 is

synthetically attractive for several reasons:

• It involves a minimum of three discreet substitution reactions (intramolecular

nucleophilic substitution to give reactive gem-dichloroepoxide intermediate 4, inter- or

intramolecular nucleophilic substitution and chloride elimination to produce 5, and nucleophilic

acyl substitution to afford 6) in a one-pot process.

• The wide variety of heteroatom nucleophiles compatible with the necessary reaction

conditions provides access to a broad range of α-substituted carboxylic acid derivatives in a

multi-component reaction process.

• The reactions are typically conducted in inexpensive aqueous or lower alcohol solvents

(neat or with an organic co-solvent depending upon substrate solubility and nucleophile

compatibility), and the by-products are H2O and NaCl under most conditions.

• The tolerance of protic media offers operational simplicity relative to typical epoxide

substitution reactions.

• The gem-dichloroepoxide intermediates (4) are inherently reactive and do not require the

addition of strong Lewis or Brönsted acids for substitutions to occur.

Disubstituted trichloromethyl carbinols (2 where R1 or R2 = H) used in Jocic-Reeve reactions

are prepared in high yields by aldehyde additions to trichloromethide, from treatment of

carbanions with chloral, or by reduction of trichloromethyl ketones, among other approaches.6

Due to the poor nucleophilicity of trichloromethide, from both steric and electronic perspectives,

the preparation of many tertiary trichloromethyl carbinols (2 where R1 and R2 = alkyl or aryl) by

ketone additions to trichloromethide generally results in lower yields compared to additions by

aldehydes. However, tertiary trichloromethyl carbinols more readily form gem-dichloroepoxides

than their secondary counterparts (thereby allowing the Bargellini reaction to proceed without

isolation of 2), and the resulting 2,2-disubstituted-1,1-dichloroepoxides (4 where R ≠ H) are

more stable and less prone to side reactions than the kinetically reactive 2-monosubstituted

species (4 where R1 or R2 = H).7 Synthetic applications involving gem-dichloroepoxide

intermediates reported in publications during the past decade (2001-early 2011) are the focus of

this review. More details related to each named reaction are supplied in each respective section.

2. Jocic (Jocic-Reeve) Reactions

The Jocic reaction,1 or preferably the Jocic-Reeve reaction considering Wilkins Reeves’ seminal

contributions to both the mechanistic understanding and development of applications of the

original Jocic reaction,5,8,9 is a powerful method for the preparation of a variety of α-substituted

carboxylic acid derivatives and heterocycles. The reaction proceeds through a gem-



dichloroepoxide intermediate and was first disclosed by Zicojin Jocic in 1897. He reported a

preparation of 2,2,2-trichloro-1-phenylethanol and its unexpected conversion to 2-chloro-2-

phenylacetic acid in 22% yield upon treatment with aqueous KOH.1 Jocic’s publication appeared

nine years prior to Bargellini’s,3b which also involved preparation of a product proceeding

through a gem-dichloroepoxide intermediate. However, Link disclosed a Bargellini-type reaction

in an 1894 patent application, and hence, might have been the first to report a method involving a

gem-dichloroepoxide.3a Wilkins Reeve conducted extensive mechanistic investigations on the

original reaction reported by Jocic as well as new conversions of trichloromethyl carbinols into

2-substituted carboxylic acids and heterocycles between 1960-1980.5,8,9 Although Corey and

Link are duly credited with the preparation of α-amino acids from trichloromethyl carbinols (the

Corey-Link reaction, vide infra), Reeve appears to be the first to prepare α-amino acids in a

Jocic-type process, although his syntheses were racemic.9 Researchers have expanded Jocic-

Reeve reactions considerably in scope and breadth since Reeve’s pioneering investigations.

Advances and applications since 2001 are the focus of this section.

In 2004, Blanchet and Zhu reported the preparation of several substituted 2-imino-4-

thiazolidinones (10) by way of the Jocic-Reeve reaction (Scheme 2).10 The authors significantly

improved upon Reeve’s reported yield for the synthesis of 2-imino-5-phenylthiazolidin-4-one8d

after conducting an extensive survey of bases and solvents. Optimal conditions required

treatment of 2,2,2-trichloro-1-phenylethanol with thiourea using four equivalents of NaOH in

DME-H2O. The secondary trichloromethyl carbinols (unlike tertiary trichloromethyl carbinols,

vide supra) did not react appreciably when treated with DBU in methyl alcohol or when

introduced to base in aprotic media. The authors also established a one-pot conversion of

aldehydes to 10, albeit in lower yields relative to the two-step approach.

Scheme 2. Preparation of 2-imino-4-thiazolidinones (10) by a Jocic-Reeve reaction.

Stick and coworkers surveyed the reactions of five nucleophiles with trichloromethyl-α-D-

allofuranose derivative 11 in methyl alcohol using DBU, rather than hydroxide, as the base.11

These modified Jocic-Reeve reaction conditions, analogous to those introduced by Dominguez in

the so-called modified Corey-Link reaction,4b produced several interesting α-substituted methyl



esters 12 in moderate to high yields (Table 1). Notably, fluoride product 12b was prepared in

high yield using CsF as a nucleophile source. Such conditions proved superior to those employed

by Oliver and coworkers in their earlier preparations of α-fluorocarboxylic acids by Jocic-Reeve

reactions,12 although Oliver surveyed less compliant disubstituted trichloromethyl carbinols

rather than 11, which proceeds through an uncharacteristically isolable gem-dichloroepoxide

intermediate during the generation of 12.

Table 1. Modified Jocic-Reeve reaction of 11 with various nucleophiles

Entry Reagent X Product (12) Yield (%)

1 - Cl 12a 83

2 CsF F 12b 85

3 NaOMe OMe 12c 54

4 NaCN CN 12d 80

5 KOCN NHCO2Me 12f 50

Matsunaga, Shibasaki, and coworkers described a highly diastereoselective synthesis of -

substituted-β-aminotrichloromethyl ketones via a Mannich-type reaction.13 The β-amino ketones

were readily reduced to syn- or anti-aminotrichloromethyl alcohols (13) and then treated with

sodium hydroxide in DME:H2O to afford substituted azetidine-2-carboxylic acids (e.g., 15)

(Scheme 3). Both cis- and trans-carboxylic acid epimers of 15 were accessible from the

corresponding anti-1,3- or syn-1,3-aminoalcohol diastereomers, respectively. The resulting acids

were O-methylated prior to isolation to afford readily handled methyl esters. The combined

yields for the Jocic-Reeve reactions and subsequent methylations ranged from 57-72%.

Scheme 3. Diastereoselective synthesis of substituted azetidine-2-carboxylic acids by an

intramolecular Jocic-Reeve reaction.



During the past several years, our group has had an interest in extending the scope of the

Jocic-Reeve reaction. Our first investigation concerned the regioselective substitution of alkenyl

gem-dichloroepoxides derived from allylic trichloromethyl carbinols using various

nucleophiles.14 In that study, and in reactions since, we found that reagents which are poorly

nucleophilic in protic media, such as hydroxide, preferentially undergo SN2’ reactions with the

intermediates (17) to give -substituted enoic acids 19 (Scheme 4). However, nucleophiles that

are modest hydrogen bond acceptors, including thiolates, selenides, and azide, strongly prefer an

SN2 pathway to furnish 18. Some nucleophiles, including alkoxides, amines, and borohydrides,

generally offer poor regioselectivity.

Scheme 4. Investigation of regioselective substitution involving alkenyl gem-dichloroepoxides

(17).

We have also exploited the reactivity of gem-dichloroepoxide intermediates in the

development of convenient and inexpensive one-carbon homologation-functionalization

reactions. The conversion of aldehydes (20) to trichloromethyl carbinols (7) followed by

treatment with NaBH4 in alkaline tert-butyl alcohol or with sodium phenylseleno(triethyl)borate

complex, prepared in situ, in ethyl alcohol15 affords high yields of homologated carboxylic acids

21 (Scheme 5).16 The approach is amenable to homologation-functionalization of (hetero)aryl,

alkyl, and alkenyl aldehydes, and even sensitive enolizable aldehydes with α-stereocenters. We

have recently developed a modified Jocic-Reeve reaction that affords homologated primary,

secondary, or tertiary amides, including Weinreb amides, in high yields under similar

conditions.17 We have also devised the first one-pot preparation of trichloromethyl carbinols

from primary alcohols.18 Thus, one-carbon homologated acids or amides can now be formed

from most primary alcohols or aldehydes in just two operational steps.



Scheme 5. Two-step homologation-functionalization of aldehydes.

3. Corey-Link and Modified Corey-Link Reactions

E. J. Corey and John Link published research that evolved and popularized the Jocic-Reeve

reaction. In 1992, the authors reported a convenient and mild method of preparing racemic

trichloromethyl carbinols from aldehydes under effectively neutral conditions,2a they published

the first enantioselective approach to trichloromethyl carbinols by way of chiral oxazaborolidine

reductions of trichloromethyl ketones,2b and they provided a route to artificial chiral α-amino

acids that rivals the most popular and versatile approaches of the past two decades.2c The

extension of the Jocic-Reeve reaction to the asymmetric synthesis of α-azido acids is commonly

referred to as the Corey-Link reaction.4b It is important to note that stereochemical integrity of

the intermediate α-substituted acid chloride (5) is typically preserved in these reactions (clean

inversion of configuration in 4 and little or no ketene formation/racemization thereafter) despite

the use of KOH in DME/H2O or other protic media.

Dominguez and coworkers reported a modification of the Corey-Link reaction wherein

hydroxide is substituted with DBU in a lower alcohol (for example, MeOH or EtOH) for the

generation of the gem-dichloroepoxide, and NaN3 and catalytic 18-crown-6 are included for the

azidation step.4b Under these milder, anhydrous conditions, α-azidoesters are formed rather than

the acids created by the original Corey-Link approach. The Dominguez “modified Corey-Link

reaction”, as it is commonly tagged, has largely supplanted the original 1992 protocol. The

method has been successfully applied to the synthesis of disparate targets throughout the first

decade of the new millennium as highlighted in this section.

In 2001, Aitken and coworkers compared the yields and enantiomeric excesses arising from

the conversion of (R)-2,2,2-trichloro-1-phenylethanol into (S)-2-phenylglycine by the Corey-

Link approach.19 The authors established that the highest yields were obtained when four

equivalents of NaOH or more than one equivalent of DBU was used. However, significant

racemization was noted when hydroxide bases were employed, whereas the product was

obtained in >90% e.e. when substrates were treated with slightly more than one equivalent of

DBU. It is important to note that racemization when using hydroxide is not a general drawback

the Corey-Link reaction, but rather, it appears to be restricted to select α-azido products or

reaction intermediates.

Romo and coworkers have developed a number of elegant synthetic methods starting from β-

lactones, including chiral Wynberg lactone (22).20 The masked chiral trichloromethyl carbinol in

readily accessible (R)- or (S)-22 is revealed by hydride reduction or other common nucleophilic



acyl substitution reactions. Subsequent treatment in a Jocic-Reeve or Corey-Link reaction affords

products with expanded complexity in a minimal number of operations. In 2002, the Romo group

reported a two-step preparation of (S)-26 from (R)-22 by way of a hydride reduction, Corey-Link

reaction, intramolecular O-acylation sequence followed by an optimized lactone workup

procedure (Scheme 6).20b Chiral GC analysis indicated that the product contained only ~2.5%

racemized α-azidolactone (R)-26. Romo also highlighted an approach to natural amino acid 28

beginning from (R)-22. The sequence featured the Corey-Link amino acid synthesis with a

Staudinger reduction modification in the final step.

Scheme 6. Novel Corey-Link reactions beginning from Wynberg lactone(22).

Nielsen and coworkers prepared a bicyclic analog of the anti-HIV drug AZT by

incorporating a modified Corey-Link reaction in a key step.21 Starting from D-arabinose, the

researchers prepared trichloromethyl carbinol 29 from the corresponding ketone then

transformed 29 into 30 in high yield and without epimerization (Scheme 7). Elaboration of 30 led

to creation of nucleoside analog 31 and its α-anomer.

Scheme 7. Preparation of azido-nucleoside analogs via a modified Corey-Link reaction.

A useful approach to the synthesis of various carbohydrate α-amino acids and esters was

relayed by Stick and coworkers in two papers published in 2004.22 Similar to Nielsen, et al.,21 the

researchers converted carbohydrate ketones into asymmetric trichloromethyl carbinols (e.g., 29)

through substrate-controlled addition of lithium trichloromethide. The resultant trichloromethyl



alcohols were subjected to modified Corey-Link conditions to obtain α-azidoesters and acids,

after ester hydrolysis, and α-aminoesters, after azide reduction, in good yields and with high

stereocontrol (Scheme 8). Several furanose and pyranose analogs were prepared along with

azidonucleoside 36. The carbohydrate α-amino acids were also subsequently coupled to furnish

novel carbohydrate oligopeptides.23

Scheme 8. Preparation of azido- and amino acid analogs of carbohydrates and of nucleoside 36.

Pedregal and Prowse at Eli Lilly & Co. synthesized a racemic fluorinated analog (39) of

metabotropic glutamate receptor agonist LY354740 by taking advantage of the stereoselective

modified Corey-Link protocol.24 Attempts to prepare the amino acid functionality by way of

Strecker or Bucherer-Berg reactions proved problematic. However, the modified Corey-Link

reaction proceeded in 89% yield without epimerization and allowed for generation of targeted

amino acid products (39) after azide reduction and ester hydrolysis (Scheme 9).

Scheme 9. Synthesis of fluorinated amino acid 39 involving a modified Corey-Link reaction.

Schafmeister and coworkers applied the modified Corey-Link and the original Corey-Link

procedures in separate syntheses of precursors (41 and 43) en route to two cyclic bis-amino acid

monomers (Scheme 10).25 It is notable that the benzyl ester in 42 was not saponified during the

transformation to 43. Once prepared, the cyclic monomers 41 and 43 were employed to fashion



spatially defined spiro-ladder oligomers for use as functionalized nanostructures in molecular

recognition applications.

Scheme 10. Synthesis of -azidocarboxylic acid derivatives 41 and 43 by Corey-Link reactions.



Scheme 11. Key steps to advanced intermediate 45 in Romo’s syntheses of schulzeines B and C.

Recently, Liu and Romo described their enantioselective synthesis of potent α-glucosidase

and viral neuraminidase inhibitors schulzeines B and C.26 A key step in the approach was a

planned Corey-Link reaction/intramolecular amidation to fashion the α-amino -lactam.

However, initial treatment of 44 with NaOH and NaN3 in DME/H2O afforded undesired

intramolecular Jocic-Reeve reaction product 47 rather than the desired intermolecular azide

substitution-intramolecular N-acylation target 45 (Scheme 11). Protection of the

tetrahydroisoquinoline secondary amine followed by a Corey-Link reaction, amine deprotection,

and lactamization using diphenylphosphoryl azide (DPPA) provided key intermediate 45 en

route to successful attainment of the individual epimeric marine alkaloids.

4. Bargellini Reactions

The Bargellini reaction is a multicomponent coupling reaction that involves the treatment of in

situ-generated trichloromethide with acetone or another sterically accessible ketone and a

heteroatom nucleophile to form 2-heterosubstituted-2,2-dialkylcarboxylic acid (2-

heterosubstituted isobutyric acid) derivatives.3 The product is formed by way of regioselective

addition to an intermediate gem-dichloroepoxide (Scheme 1). In general, alkyl aldehydes are not

compatible with this reaction primarily due to competing aldol condensation and the relatively

slow rate of dichloroepoxide formation from any formed secondary trichloromethyl alkoxide.7

However, when ketones are used, the protocol offers rapid, convenient, and cost effective access

to 2-heterosubstituted-2,2-dialkylcarboxylic acid derivatives and heterocycles. Unlike research

related to the Jocic-Reeve or Corey-Link reactions, many of the advances associated with

Bargellini couplings have been reported by researchers in the pharmaceutical industry. Several

manuscripts published during the past decade expanded the breadth of the reaction by

highlighting alternative nucleophiles and ketones amenable to the reaction conditions. As a

result, the Bargellini reaction now offers a one-pot, proven route to the preparation of a broad

range of hindered carboxylic acids and acid derivatives. Applications and modifications reported

since 2001 are highlighted in this section.

John Lai of BF Goodrich developed several extensions to, and revealed applications of, the

Bargellini reaction during the past three decades.27 In 2001, he reported the use of a hindered,

activated arene, 2,6-di-tert-butylphenol (48), as a carbon nucleophile in a clever one-pot

Bargellini reaction to create a series of hindered 2,6-di-tert-butyl-4-(1,1-dialkyl-1acetamide)-

phenols 50 (Scheme 12).28 Many of the products afforded persistent phenoxy radicals with half-

lives appreciably longer than that of 2,4,6-tert-butylphenoxy radical.



Scheme 12. Combination of Bargellini and Friedel-Crafts alkylation reactions to prepare

phenoxy radical precursors 50.

Abraham and coworkers applied a Bargellini reaction to a gram-scale synthesis of 52, a

known allosteric effector of hemoglobin (Hb) (Scheme 13).29 Compound 52 served as a lead for

amino acid conjugates expected to act as new allosteric modifiers of Hb. Although a Bargellini

protocol was initially adopted to prepare 52, the researchers ultimately performed O-alkylation

reactions with ethyl-1-bromocyclopentane carboxylate for larger scale preparations of 52 en

route to their series of amino acid conjugates.

Scheme 13. Preparation of bioactive amino acid conjugate precursors 53 by a Bargellini reaction

In 2004, researchers at GlaxoSmithKline reported that use of 2-bromo-2-methylpropanoic

acid under alkaline conditions afforded valuable 2-methyl-2-aryloxypropanoic acid derivatives

on gram to multi-kilogram scales.30 They noted that employment of 2-bromo-2-methylpropanoic

acid proved superior to other conditions, including those used in the Bargellini reaction, because

2-bromo-2-methylpropanoic acid lessens safety concerns associated with possible CHCl3

regeneration, mesityl oxide formation (from acetone), and the exothermicity associated with the

introduction of 1,1,1-trichloro-2-methyl-2-propanol (chloretone) commonly employed in the

Bargellini protocol. However, researchers at Merck thoroughly investigated several procedures

for the preparation of dual PPAR α/ agonist 54 and found the direct conversion of

benzisoxazole 53 to target 54 by way of an optimized Bargellini reaction offered superior results

in terms of yield and step economy (Scheme 14).31 Mesityl oxide formation and exothermicity

were not problematic under the optimized conditions. During their investigation, the authors also

established the half-life of the presumptive kinetically reactive 1,1-dichloro-2,2-dimethyloxirane



in basic acetone as approximately five minutes based upon ReactIR studies. The oxirane

intermediate could not be observed by NMR spectroscopy, presumably due to the consistently

low concentration of the reactive dichloroepoxide throughout the course of the reaction. The

Merck finding is consonant with our observations involving attempted detection of gem-

dichloroepoxide intermediates by NMR spectroscopy during several of our studies.

Scheme 14. Optimized synthesis of dual PPAR α/ agonist 54 exploiting a Bargellini reaction.

Venkateswaran and coworkers reported applications of the Bargellini reaction in the

preparation of helianane 57 and several heliannuols (Scheme 15).32 Treatment of coumarins or

dihydrocoumarins with chloroform and aqueous NaOH in acetone afforded diacids (56) in 65-

75% yields. Elaboration of one of the diacid products afforded marine metabolite helianane (57)

in five additional steps. Related efforts with other substituted coumarins furnished sunflower

allelochemicals heliannuols C (58) and A (59) along with enantiomeric and epimeric

stereoisomers.

Scheme 15. Bargellini reactions in key early steps of conversions of coumarin derivatives to

helianane (57) and stereoisomers of heliannuols C (58) and A (59).



Butcher and Hurst showed that weakly nucleophilic anilines and amine-substituted

heterocycles can be used in Bargellini reactions to prepare hindered α-amino acid derivatives in a

single step (Scheme 16).33 Product yields were highly dependent upon the amine nucleophile

employed. However, the step-economy of the approach offers clear advantages over many other

strategies as illustrated by the authors’ comparative synthesis of a racemic carfentanil analog.

Scheme 16. Representative preparation of a hindered α-amino acid (62) by way of a Bargellini

reaction involving an amino heterocycles (60).

The trichloromethide involved in the Bargellini reaction is typically generated by

deprotonation of chloroform with sodium hydroxide. However, use of NaOH can compromise

yields with substrates that are particularly prone to hydrolysis. Rohman and Myrboh recently

reported that solid potassium fluoride coated with alumina (KF/Al2O3) serves as a viable

replacement for sodium or potassium hydroxide in Bargellini condensation reactions (Scheme

17).34 Notably, under these conditions the reaction was highly successful in toluene but not in

ethyl alcohol. The authors evaluated Bargellini reactions using substituted phenols, thiophenols,

anilines, or 2-aminopyridine (63) as the nucleophile involved in substitution with the

intermediate gem-dichloroepoxide and cyclohexanone or Boc-protected piperidine-4-one (64) as

the initial carbonyl component. Yields of products 65 ranged from 56-91% and are comparable

to those reported in reactions conducted with hydroxide as the base.

Scheme 17. Alternative to hydroxide or DBU as base in Bargellini reactions

Yu and coworkers disclosed that α-hydroxy acids could be prepared by treating simple

ketones or aldehydes, including enolizable aldehydes, with sodium trichloroacetate and catalytic

tetrabutylammonium bromide in chloroform/water using 70 W microwave irradiation (Scheme



18). After trichloromethylation was judged complete (5-10 minutes), excess sodium hydroxide

was added to the reaction mixture, and α-hydroxy acid (67) formation was promoted by further

irradiation at 100 W for 30-40 minutes.35 This expedient protocol offered promising yields (50-

80%) for nine tested substrates, but cinnamaldehyde displayed disappointing results. The method

appears to be compatible with many aldehydes, and it obviates the traditional isolation of

secondary trichloromethyl carbinols. Hence, the approach is a microwave-assisted hybrid of the

Bargellini and Jocic-Reeve reactions.

Scheme 18. One-pot microwave-promoted synthesis of 2-hydroxycarboxylic acids (67) from

aldehydes or ketones.

5. Conclusions

Diverse 2-substituted acids, esters, amides, and heterocycles are readily accessible by way of

reactions involving gem-dichloroepoxide intermediates. Jocic-Reeve, Corey-Link, and Bargellini

reactions are likely to gain increasing exposure as powerful tools in synthesis based upon the

array of products attainable through these methods and the efficiency and operational simplicity

of the associated protocols. During the past decade, great strides have been made in clarifying

the scope and limitations of these named reactions and in tailoring the conditions to create step-

economical methods for the synthesis of targets important to industry, medicine, and biology. It

is exciting to ponder what the next decade of advances in reactions involving gem-

dichloroepoxide intermediates might reveal.

6. Acknowledgements

We are grateful to the National Science Foundation CAREER program (CHE-0847686) and the

American Chemical Society Petroleum Research Fund (44401-G1) for support of our work

involving gem-dichloroepoxide intermediates.

7. References

1. Jocic, Z. Zh. Russ. Fiz. Khim. Ova. 1897, 29, 97.



2. (a) Corey, E. J.; Link, J. O.; Shao, Y. Tetrahedron Lett. 1992, 33, 3435. (b) Corey, E. J.;

Link, J. O. Tetrahedron Lett. 1992, 33, 3431. (c) Corey, E. J.; Link, J. O. J. Am. Chem. Soc.

1992, 114, 1906.

3. (a) Link, G. German Patent 80,986 (July 14, 1894) from: Chem. Zentr. 1895, 66(II), 70. (b)

Bargellini, G. Gazz. Chim. Ital. 1906, 36, 329.

4. (a) To our knowledge, the first instance of an intermolecular substitution reaction involving

a gem-dichloroepoxide intermediate being classified as a Jocic reaction was from: Oliver, J.

E.; Schmidt, W. F. Tetrahedron: Asymmetry 1998, 9, 1723. Reeve also referred to a Jocic

reaction, in a more restrictive sense, in reference 2 of: Reeve, W.; McKee, J. R.; Brown, R.;

Lakshmanan, S.; McKee, G. A. Can. J. Chem. 1980, 58, 485. An earlier reaction reported as

a Jocic reaction did not involve a gem-dichloroepoxide intermediate or relate to the chemistry

described herein: Kibina, I. Y.; Shchelkunov, A. V.; Martynov, V. F. Trudy Khimiko-

Metallurgicheskogo Instituta, Akademiya Nauk Kazakhskoi SSR 1972, 18, 17. (b) To our

knowledge, the first instance of a reaction involving a gem-dichloroepoxide intermediate

being classified as a Corey-Link reaction was from: Dominguez, C.; Ezquerra, J.; Baker, S.

R.; Borrelly, S.; Prieto, L.; Espada, C. M.; Pedregal, C. Tetrahedron Lett. 1998, 39, 9305. (c)

To our knowledge, the first instance of a reaction involving a gem-dichloroepoxide

intermediate being classified as a Bargellini reaction was from: Rychnovsky, S. D.;

Beauchamp, T.; Vaidyanathan, R.; Kwan, T. J. Org. Chem. 1998, 63, 6363.”

5. (a) Reeve, W. Synthesis 1971, 131. (b) Reeve, W.; Bianchi, R. J.; McKee, J. R. A J. Org.

Chem. 1975, 40, 339. (c) Reeve, W.; McKee, J. R.; Brown, R.; Lakshmanan, S.; McKee, G.

A. Can. J. Chem. 1980, 58, 485. (d) Reeve, W.; Steckel, T. F. Can. J. Chem. 1980, 58,

2784.

6. For two excellent reviews concerning preparations and reactions of trichloromethyl

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Recent applications of gem-dichloroepoxide intermediates in synthesis

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